tbuckley/cabot-search huggingface dataset:
PATH-30. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND IMMUNE CELL STATES IN GROUP3 AND GROUP 4 MEDULLOBLASTOMA
Authors: Saleembhasha Asanigari, Bharati Mehani, Di Wu, Hye-Jung Chung, Kenneth Aldape
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is a heterogeneous malignant childhood brain cancer, classified into four molecular subgroups, WNT, SHH, Group3, and Group4, based on transcriptional, genetic, and clinical features. We aimed to understand the tumor microenvironment of Group 3 and Group 4 tumors utilizing single-cell transcriptome data. We identified four neoplastic cell states, including stemness (TNF-α), proliferative, mesenchymal and quiescence, and 11 broad lymphoid and myeloid cell types from single-cell transcriptomes. We applied CIBERSORTx to enumerate cell type proportion and CODEFACS on 73 bulk MB RNAseq profiles to determine cell type-specific abundance and gene expression profiles. We noted significant associations (both positive and negative) between the abundance of neoplastic cell states and microenvironmental cell types in both group3 and group4 MB. For example, the invasive cell state negatively correlated with dendritic cells in Group3 and Group4 tumors, but the invasive cell state was oppositely correlated with a macrophage subset in group 3 versus group 4 tumors, Survival analysis showed a significant association of higher proliferative cell state with poorer survival in Group3 MB while in group4 elevated invasive cell state, as well as elevated α, NK, and CD4-T cell abundance showed trends for poorer prognosis. Using Ecotyper, we determined cellular ecotypes based on cell type-specific transcriptome states. An ecotype containing B cell, hematopoietic, dendritic, and proliferative cell states was associated with poor prognosis in group3 and group4 tumors. We further analyzed ligand-receptor interaction between cell type states of poor prognosis ecotype; and found several interactions between ligands from immune cells (SEMA4G, LAMB2) and receptors on neoplastic cells (PLXNB2). Conversely, extracellular matrix ligands on neoplastic cells (COL1A1/2 and FN1) were found on this analysis potentially associated with integrin receptors on immune cells. Overall, our study highlights the potential biologic and clinical significance of neoplastic and immune cell states in group3/4 MB.
CTNI-53. PNOC014: PHASE IB STUDY RESULTS OF DAY101(TOVORAFENIB) FOR CHILDREN WITH LOW-GRADE GLIOMAS (LGGS) AND OTHER RAS/RAF/MEK/ERK PATHWAY-ACTIVATED TUMORS
Authors: Karen Wright, Cassie Kline, Mohamed Abdelbaki, David Ebb, Elias Sayour, Jennifer Elster, Sarah Leary, Matthew Miller, Ashley Margol, Kenneth Cohen, Lindsay Kilburn, Anne Bendel, Pei-Chi Kao, Clement Ma, Wendy London, Sabine Mueller, Michael Prados, Daphne Haas-Kogan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA). METHODS Eligible patients were &amp;lt; 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or &amp;gt; 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1. RESULTS We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia). CONCLUSIONS Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA &amp;lt; 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA &amp;gt;1.5m2.
CNSC-16. BIDIRECTIONAL SIGNALING BETWEEN GLIOBLASTOMA AND NEURAL PROGENITORS EXPLORED WITH CELL-SPECIFIC PROTEOMICS RESULTS IN INCREASED TUMOR MALIGNANCY AND ALTERED NEUROGENESIS IN THE SUBVENTRICULAR ZONE
Authors: Emily Norton, Lauren Whaley, Vanessa Jones, Mieu Brooks, Natanael Zarco, Marissa Russo, Paula Schiapparelli, Guadalupe Sanchez, Andres Ramos-Fresnedo, Wilfried Rossoll, Kaisorn Chaichana, Panos Anastasiadis, Alfredo Quiñones-Hinojosa, Hugo Guerrero-Cazares
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary neoplasm of the central nervous system. The location of GBM contributes significantly to patient outcomes, where tumors contacting the lateral ventricles (LVs) have increased expression of stem cell genes, increased incidence of distal recurrence, and decreased overall survival. While the reasons for these findings are not fully understood, we hypothesize they arise due to interactions with the subventricular zone (SVZ), the largest neurogenic niche in mammals. We examined bidirectional signals between GBM cells and neural progenitor cells (NPCs) in vitro and in vivo using a combination of patient-derived intraoperative samples, preclinical animal models, and the methionine tRNA synthetase L274G (MetRS*) nascent proteomic labeling system, which allows for cell-specific proteomics analysis from complex in vivo systems. In co-culture with NPCs, GBM cells increase their viability, proliferation, migration, and expression of malignancy-promoting proteins, including migratory proteins such as TAGLN, PALLD, and STAT1. In vivo, tumor proximity to the SVZ results in increased proliferation, increased expression of stemness markers, decreased survival, and altered tumor-specific proteome. We then examined the reciprocal effect of GBM cells on NPC biology. In vitro and in vivo, GBM cells decreased NPC proliferation and induced decreased neuronal maturation of NPCs. To determine NPC proteomic changes in vivo, we created a transgenic mouse line Nestin-CreERT2; STOPflox R26-MetRS L274G, where upon tamoxifen administration Nestin+ NPCs express GFP and MetRS*. Our results indicate that LV-proximal GBM induces decreased expression of neuronal maturation proteins such as Eml1, VGLUT1, and EAAT2, and an increase in pro-migratory factors such as Lamc1 in NPCs. In conclusion, there are bidirectional proteomic interactions between GBM cells and NPCs that contributes to altered neurogenesis and increased tumor malignancy of LV-proximal GBM. The signaling factors identified in our studies will result in identification of novel therapeutic targets for GBM.
QLTI-21. SAFETY OF THE UTILIZATION OF TELEMEDICINE FOR BRAIN TUMOR NEUROSURGERY FOLLOW-UP
Authors: Alexis Morell, Nitesh Patel, Dominique Higgins, Tiffany Eatz, Adam Levy, Daniel Eichberg, Ashish Shah, Michael Kader, Alexis Morell, Michael Ivan, Ricardo Komotar
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND There is a need to evaluate the outcomes of patients who underwent brain tumor surgery and were followed by telemedicine or in-person consults during the COVID-19 pandemic. METHODS We retrospectively included all patients who underwent surgery for brain tumor resection by a single neurosurgeon at our Institution from the beginning of the COVID-19 pandemic restrictions (March 2020) to August 2021. Outcomes were assessed by stratifying the patients using their preference for follow-up method (telemedicine or in-person). RESULTS Three-hundred and eighteen (318) brain tumor patients who were included. The follow-up method of choice was telemedicine in 185 patients (58.17%), and in-person consults in 133 patients. We found that patients followed by telemedicine lived significantly farther, with a median of 22.23 miles, compared to a median of 36.34 miles in the TM cohort (p = 0.0025). When comparing visits to the emergency department (ED) within 30 days after surgery, and we found no statistical difference between the TM and the IP group (7.3% vs 6.01%, p=0.72). Readmission rates, wound infections and 30-day mortality were similar in both cohorts. These findings were also consistent after matching cohorts using a propensity score. The percentage of telemedicine follow-up consults was higher in the first semester (73.17%) of the COVID-19 pandemic, compared to the second (46.21%) and third semesters (47.86%). CONCLUSIONS Telehealth follow-up alternatives may be safely offered to patients after brain tumor surgery, thereby reducing patient burden in those with longer distances to the hospital or special situations as the COVID-19 pandemic.
CSIG-32. ABL1 AND 2 DRIVE MEDULLOBLASTOMA PROLIFERATION AND ADHESION IN LEPTOMENINGEAL DISSEMINATION
Authors: Eric Thompson, Jill Jones, Reb Kornaherns, Steven Zhang
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The molecular mechanisms that drive leptomeningeal dissemination (LD) of medulloblastoma (MB) are largely unknown. The Abelson (ABL) family kinases, originally identified as oncogenes in leukemia, play an important role in lung cancer cell migration, invasion, cell adhesion, and chemotherapy resistance. The objective of this work was to elucidate the role of ABL kinases in MB LD. METHODS ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of MB LD. RESULTS ABL1 and ABL2 levels were significantly higher in MB patients with LD than without (p=2.6x10-10 and 7.2x10-7, respectively) and overall survival was significantly reduced in patients with high ABL1 and 2 expression (p=0.019 and 0.00027, respectively). In vitro pharmacologic inhibition and genetic knockdown of ABL1 and ABL2 in Group 3/4 MB resulted in statistically significant cell death, decreased adhesion to vitronectin (a key leptomeningeal extracellular matrix [ECM] protein), decreased migration through ECM extract, and decreased c-myc expression in multiple MB cell types. In mouse models of MB LD, ABL1/2 knockdown significantly decreased LD as determined by bioluminescence and improved overall survival (p=0.0044). Pharmacologic inhibition of ABL1/2 using nilotinib resulted in improved median overall survival (64 vs. 76.5 days). CONCLUSIONS ABL1 and ABL2 are preferentially expressed in patients with MB LD at diagnosis and are associated with poor survival. Both genetic inactivation and pharmacologic inhibition of ABL1 and 2 decreased MB LD in vitro and in vivo, likely via reduction of c-myc signaling. This preliminary work suggests a key role for ABL1/2 in driving MB LD.
EPCO-30. IDENTIFICATION OF PRECANCEROUS CELLS LEADING TO INTRATUMORAL HETEROGENEITY IN GLIOBLASTOMA
Authors: Hyun Jung Kim, Do Hyeon Cha, Keon Woo Kim, Myeong Heui Kim, Jung Won Park, Ja Hye Kim, Seon Jin Yoon, Seok-Gu Kang, Jeong Ho Lee
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Although multiple oncogenic mutations have been identified in neural stem cells of the subventricular zone (SVZ) in humans, the dynamic process of how tumor initiation begins with a mutation-harboring stem cells remains elusive. To better understand how GBM evolves, we analyzed longitudinal transcriptomic changes of mutation-harboring stem cells using a spontaneous, somatic GBM animal model with EGFRvIII, TP53, PTEN mutations. Using single-cell RNA sequencing, we have identified precancerous cell populations originating from oligodendrocyte precursor cells, with increased proliferation and decreased capacity to differentiate into oligodendrocytes. The precancerous cell populations undergo malignant transformation to become heterogeneous cancer cells characterized by immune evasion, mesenchymal transition, and cell cycle. We further identified the precancerous populations in the SVZ of human GBM patients with chromosomal aberrations. Our findings suggest that GBM evolution is closely related to oligodendrocyte precursor cell specification, and the time-dependent transcriptomic changes in precancerous cells is a novel therapeutic target for tumor evolution.
RADT-30. RADIATION INDUCED MENINGIOMA IN BACKGROUND OF CHILDHOOD CRANIAL IRRADIATION: A CASE SERIES
Authors: Sunnia Gupta, Angela Swampillai, Lucy Brazil, Omar Al-Salihi
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Cranial irradiation as part of prophylactic (PCI) or radical treatment for childhood malignancies can be associated with late consequences such as radiotherapy induced meningioma. METHODS We are reporting 5 such patients treated at our institute. RESULTS Case 1: 24y female received PCI for Acute Lymphoblastic Leukemia at the age of 2, and developed right frontal meningioma which was resected and pathology confirmed grade 2 atypical meningioma. It was treated with radiotherapy 60Gy/30fr and 2 year follow up scans remain stable. Case 2: 31y male received PCI as a child, and developed parieto-occipital meningioma which was excised multiple times. Pathology revealed Grade 2 atypical meningioma and was treated with radiotherapy 60Gy/30fr. Follow up scans 3.5 yrs later remain stable.Case3: 37y male received PCI at the age of 3, and developed multiple site meningiomas which were excised. Pathology showed likely Grade 2 meningioma. The sphenoid wing lesion progressed 2 years later, was re-excised and treated recently with radiotherapy 60Gy/30fr. Case 4: 52y female treated with radiotherapy for retinoblastoma at the age of 6-8 wks, developed left sphenoid wing meningioma which was resected and pathology revealed malignant meningioma. Radiotherapy 60Gy/30fr was recently completed.Case 5: 24y female treated with radiotherapy for medulloblastoma at the age of 5, developed meningiomas at multiple sites. Over the span of 10 years the frontal and clinoid lesions increased in size, and were treated with SRS/SRT recently. CONCLUSION All patients had background of cranial radiation and developed meningioma with latency period ranging 19 to 52 years. It is not possible to make an inference on gender, site of meningioma or craniaI dose correlation because of small number of cases and lack of data on dose. Further research is needed on how to prevent secondary malignancies in such patients and on standard of care for secondary meningiomas.
CNSC-33. TRANSCRIPTOMIC NEURON-TUMOR INTERACTION MAPPING OF EXTRACRANIAL TUMORS AND BRAIN METASTASES
Authors: Marc Schubert, Wolfgang Wick, Thomas Kuner, Frank Winkler, Varun Venkataramani
Journal: Neuro-Oncology (2022)

Abstract Ongoing efforts in the field of Cancer Neuroscience seek to improve the understanding of neuron-cancer interactions and their effects on tumor progression. In glioma, synaptic neuronal input to tumor cells drives tumor progression and invasion. Even though neuron-cancer interactions have been described in brain metastases and extracranial tumors as well, the mechanisms of action between the nervous system and tumor cells are incompletely understood. Systematic transcriptomic analyses to detect overarching principles of neuron-tumor interaction have been lacking so far. Here, we performed focused integrative transcriptomic and proteomic analyses in more than 10 different extracranial tumor entities and brain metastases to analyse potential neuron-tumor interactions.Neurotransmitters receptor genes were heterogeneously expressed across extracranial tumor entities and brain metastases. We used Markov Affinity-based Graph Imputation of Cells to recover gene-gene relationships to robustly identify more than 50 initial gene co-expression networks (GCNs) associated with neurotransmitter genes. Molecular pathways that are associated with neurotransmitter receptor gene expression show heterogenous and overlapping neuronal gene expression programs in tumor cell subpopulations. While some GCNs showed overarching expression patterns of neuronal interactions across many entities including brain metastases as well as extracranial tumors, some GCNs were specialised signatures for certain tumor types. To characterise underlying gene regulatory networks, we performed transcription factor analyses. Certain GCNs were clearly associated with specific transcriptional regulators and known tumor biological functions. To validate our results, we further analysed the GCNs in bulk RNA datasets as well as on a protein level. We were able to identify neuronal gene expression patterns that were associated with worse survival across certain tumor entities.The results suggest that brain metastases and extracranial tumors have multiple biologically relevant mechanisms of interaction with the nervous system. These analyses are the foundation for further validation and clinical translation.
NIMG-92. DOTATATE PET/MR-GUIDED POSTOPERATIVE RADIOTHERAPY IN SUBTOTALLY RESECTED WHO-2 MENINGIOMA: EVALUATION OF PROGRESSION-FREE SURVIVAL IN A PROSPECTIVE COHORT
Authors: Jonathan Knisely, Se Jung Chang, Sean H Kim, Arsalan Haghdel, Michelle Roytman, Gabriela Madera, Rajiv Magge, Benjamin Liechty, David Pisapia, Evan Noch, Howard Fine, Susan Pannullo, Rupa Juthani, Rohan Ramakrishna, Theodore Schwartz, Philip Stieg, Babacar Cisse, Andrew Brandmaier, Nicolas Karakatsanis, Joseph Osborne, Eaton Lin, Jana Ivanidze
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Current postoperative management recommendations for meningioma lack Level 1 evidence. NRG-0539 (NCT00895622) treated recurrent WHO-1 and newly diagnosed and completely resected (by postoperative MRI) WHO-2 meningiomas with postoperative fractionated radiotherapy to 54 Gy, but 3 year PFS remained below 60%. MRI, the standard of care (SOC) for meningioma radiotherapy planning, lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. More sensitive and specific imaging biomarkers are needed to improve RT guidance and thereby clinical outcomes in meningioma. [68Ga]-DOTATATE is a PET radiotracer targeting somatostatin receptor 2 (SSTR2), a highly sensitive and specific meningioma biomarker. We developed a dedicated DOTATATE brain PET/MRI protocol allowing meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective observational trial (NCT04081701) has imaged over 90 patients with meningioma. This IRB-approved study evaluated PFS in patients with WHO-2 tumors who did not achieve GTR by [68Ga]-DOTATATE PET/MRI, managed with PET/MR guided RT, hypothesizing that the PFS of patients with STR by PET/MRI managed with PET/MR guided RT would be higher than for comparable patients enrolled on NRG 0539. METHODS 92 patients with SSTR2-positive brain neoplasms were enrolled between 9/2019 and 5/2022 and imaged according to our previously published protocol. 7 patients met inclusion criteria (WHO-2 meningioma; postoperative PET/MR with residual activity) who underwent PET/MR-guided RT, followed with SOC MRI. Kaplan-Meier survival analysis was performed. RESULTS 5/7 subjects (71%) were women; the mean age was 50.7 years. MRI follow-up data were available for a mean of 18.7 months (range: 16-24 months). All patients remain progression-free at this time; Kaplan-Meier analysis demonstrated 2-year PFS to be 100%, which is substantially higher than reported PFS in this clinical population using standard-of-care MRI-guided RT. CONCLUSIONS [68Ga]-DOTATATE PET/MR-guidance can improve PFS following postoperative RT in subtotally resected WHO-2 meningiomas.
BIOM-14. SYSTEMIC BIOMARKERS OF TUMOR BURDEN IN GLIOBLASTOMA PATIENTS
Authors: Peter Chabot, Dominique Fontaine, Carmen del Genio, Yujia Shentu, Arti Gaur
Journal: Neuro-Oncology (2022)

Abstract Glioblastomas (GBM) are Grade IV gliomas that are highly aggressive, lethal primary brain tumors. They are extremely heterogenous tumors both at a cellular and molecular level, harboring diverse oncogenes and mutated tumor suppressor genes with both inter- and intra-tumor variability in expression patterns. Currently, the presence of GBM cannot be predicted and they are diagnosed post-surgical resection by histologic evaluation of tumor tissue. There is an urgent, unmet need for the discovery of GBM-specific biomarkers that could precisely predict and monitor the presence of tumors in GBM patients. Over the last seven years we have carried out a prospective, multi-center, clinical study to longitudinally analyze tumor and plasma samples from GBM patients. We have characterized expression levels of microRNAs, mRNAs and proteins isolated from plasma samples collected from GBM patients throughout their treatment and compared these data to clinical and pathological reports for each patient. Our research has identified a set of systemic microRNAs and their targets that can be correlated to tumor burden in GBM patients. Data will be presented to demonstrate how specific sets of molecular markers and secreted proteins can track disease in GBM patients. This study provides insights into how systemically expressed biomarkers in GBM patients can be used in the development of methods for the precise assessment of disease progression and treatment efficacy while being minimally invasive and cost-effective. Combining clinicopathological findings and biomarker profiling will predict treatment outcomes and provide oncologists precise readouts for tumor burden and response to treatment. Furthermore, this research will also provide critically needed criteria for rigorous monitoring of efficacy of all new therapeutic trials for GBM.